Abstract
The effect of the combined administration of doxorubicin (DX) and verapamil (VRP) on the induction of DX resistance of B16 melanoma cells, was investigated both in vitro and in vivo. Cells grown in the presence of increasing concentrations of DX and of 1 microM VRP, tested at several passages, were more resistant than cells grown with DX alone. The treatment of B16 melanoma bearing mice with the maximal tolerated dose of DX (12 mg kg-1 i.v.) and of VRP (25 mg kg-1 i.p.) selected a line (B16-DX. VRP) completely resistant to DX after 17 transplants, while treatment with DX alone selected a DX resistant line after 27 transplants. Lung metastases were significantly lower in the B16-DX. VRP line compared to the original B16 melanoma. The results suggest that the association of VRP with DX increases the rate of resistance development to DX.
Highlights
DX was kindly supplied by Farmitalia-Carlo Erba (Milan, Italy) and was dissolved in distilled water immediately before use
The development of resistance was checked after different passages by comparing DX activity on the parallel transplanted parental B16 line and on the two treated lines designated B16-DX and B16-DX.VRP respectively
The increase of DX concentration in the medium of BI6V-DX and B16VDX.VRP led to an increase in the resistance index (RI) which was higher if cells were grown in the presence of 1 MM VRP
Summary
DrugsDX was kindly supplied by Farmitalia-Carlo Erba (Milan, Italy) and was dissolved in distilled water immediately before use. VRP was administered according to the schedule previously found effective in increasing DX activity in this tumour (Formelli et al, 1988). It was administered 3h before DX, since in vitro it potentiates DX activity in pretreated cells (Supino et al, 1986). The two lines were transplanted in mice not treated with DX for one passage before the anti-tumour activity assays. From the evaluation of the significance (Student's t test) of the difference of the tumour weights of treated and control mice 3 weeks after tumour implant a T-C>4 days corresponds to a significant reduction of tumour weight. The significance of the difference of MST in the different groups was evaluated by Student's t test
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